There are four subtypes of receptors for adenosine, designated A1, A2A, A2B, and A3. The A3 adenosine receptor is found primarily in the central nervous system, brain, testes, and the immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction (Ramkumar et al., J. Biol. Chem., 268, 16887-16890 (1993)).
It is believed that A3 adenosine receptor selective antagonists should serve as cerebroprotective, antiasthmatic, or anti-inflammatory agents. It is also believed that A3 adenosine receptor selective antagonists should serve in the treatment of glaucoma, for example, in reducing intraocular pressure. Research activity is evident in the area of A3 adenosine receptor antagonists; see, for example, U.S. Pat. Nos. 6,066,642 and 6,528,516 and WO 2008/055711. Accordingly, there is a desire to find new A3 adenosine receptor antagonists.
Further, A3 adenosine receptor partial agonists, are advantageous in cardioprotection and produce anti-ischemic effects. Partial agonists also tend to have less side effects than full agonists. In addition, partial agonists are less likely to produce desensitization of the receptor as compared to full agonists. Accordingly, partial agonists can activate the receptor for a longer duration and achieve longer lasting response. Accordingly, there is a desire to find new A3 adenosine receptor partial agonists.
In addition, full or partial agonists of the A1 AR are being considered for treatment of various conditions: seizures, stroke, diabetes, pain, cardioprotection and arrhythmias. A1 AR agonists are highly neuroprotective in ischemic and epileptic models. A1 AR agonists are also being explored for antidepressant, antianxiety, and other neuropsychiatric effects, due to their presynaptic action to decrease the release of excitatory amino acids in the brain. However, peripheral cardiovascular side effects have prevented the introduction of A1 AR agonist for treating disorders of the central nervous system (CNS). Accordingly, there is a desire to find new A1 adenosine receptor full and partial agonists.